Particles of compounds having low water-solubility are commonly used in a wide variety of applications, including ceramics, paints, inks, dyes, lubricants, pesticides, insecticides, fungicides, fertilizers, chromatography columns, cosmetics, lotions, ointments, and detergents. Aqueous dispersions of particles are used in many cases to avoid hazards such as flammability and toxicity associated with organic solvents. Such dispersions typically have a broad range of particle size.
In many cases product performance is improved by controlling the particle size distribution. In general, smaller particles of a compound will dissolve faster than larger particles of the same compounds. Control of particle size is, therefore, important in controlling the rate of solubilization.
Many drugs have been formulated as particles for controlled-release following oral administration or implantation. Particle size is one important factor affecting the release rate of these drugs. Those skilled in the art can discern other examples for using particle size to control product performance for the substances listed above.
Drugs that are insoluble in water can have significant benefits when formulated as a stable suspension of particles of less than three microns diameter. In this particulate form, the drug can be injected intravenously, circulate in blood, and be preferentially accumulated in, for example, the reticuloendothelial system, where it can facilitate normal reticuloendothelial functions such as detoxification. Alternatively, the drug can reside in the reticuloendothelial cells where it is stored until solubilized or metabolized into an active form which circulates in blood to other tissues for efficacy. This "slow" release of active drug can provide more constant drug concentrations in plasma over a period of hours, days, weeks, or months, resulting in improved therapeutic efficacy. Biodegradable particles which are radiopaque or labelled with a radioisotope are useful for diagnostic imaging of organs, such as liver and spleen, with high concentrations of fixed reticuloendothelial function.
Many advantages have already been recognized for insoluble particulate radiopaque contrast media, for example, as explained in "Improvement in Radiographic Contrast Media Through the Development of Colloidal or Particulate Media: an Analysis", by Harry W. Fischer, Journal of Theoretical Biology; 67: 653-670 (1977). More recent papers on this subject include Violante, M. R., Fischer, H. W., and Mohoney, J. A., "Particulate Contrast Media," Invest. Radiol., 15: S329 November-December 1980; and Violante, M. R., Dean, P. B., Fischer, H. W., and Mahoney, J. A., "Particulate Contrast Media for Computer Tomographic Scanning of the Liver", Invest. Radiol., 15: 171 November-December 1980.
There are enormous medical implications for the intravenous administration of drugs formulated as suspensions of particles of three microns diameter, or less, which can be accumulated by phagocytic cells and slowly solubilized for sustained release into plasma for circulation to other organs and tissues. Obvious drug classes appropriate for formulation as particulate suspensions include: antineoplastics, antimicrobials, antivirals, anticoagulants, antihypertensives, antihistamines, antimalarials, male and female contraceptives, antiepileptics, depressants and antidepressants, adrenocortical steroids, hormones and hormone antagonists, cardiac glycosides, immunosuppressants, beta-blockers, water-insoluble vitamins, sympathomimetics, hypoglycemic agents, hyperglycemic agents, analgesics, tranquilizers, mood altering drugs, and others. The treatment of deficiency diseases, alcohol abuse, drug abuse, and many others could be improved with intravenous administration of particulate suspensions of the appropriate drug. Other medical applications for particulate drug suspensions will be apparent to those skilled in the art.
Accurate control of particle size is essential for safe and efficacious use of these formulations. Particles must be less than three microns in diameter to safely pass through capillaries without causing emboli. This is critical for intravenous administration since the particles must pass through lung capillaries before reaching the fixed reticuloendothelial cells of liver and spleen. Restriction to particle diameters of 0.01-0.1 micron could result in selective accumulation of these particles in certain tissues, eg., neoplastic tissue, where capillaries are somewhat more porous than capillaries of normal tissues. Suspensions of particles with diameters greater than 10 microns could be useful for selective intra-arterial administration to purposely embolize vessels feeding abnormal tissue such as a neoplasm. Accurate and precise control of particle diameters is essential for efficacy while minimizing or avoiding adverse effects in each of these applications.
Conventional methods of making water-insoluble compounds produce particles of many different sizes, many of which are unsuitable for the purpose at hand. Mechanically sorting or separating a desired particle size from a mix of sizes is difficult and unsatisfactory. Centrifuging and filtration do not produce high yields of particles that are all precisely the same desired size.
Investigations of water-insoluble radiopaque contrast materials required uniform particles in specific sizes that were very difficult to obtain by conventional methods. Precipitation as a way of directly forming particles of a predetermined size was then investigated. Partial success was achieved with one material and one method as reported in "Particulate Contrast Media", Investigative Radiology, 15: S329 November-December 1980; but this method would not work with other materials and would not allow accurate variation and control of the particle size produced.
Further investigation led to the invention of this application, which is effective with any drug or other compound having a solubility in water of preferably less than one part per ten thousand to obtain a predetermined particle size of the water-insoluble drugs or other compounds used in aqueous dispersions.